The role of platelets in tumor growth, wound healing and other angiogenesis disease states The role of platelets in angiogenesis has been appreciated in the past both clinically and pre- clinically. We have recently published evidence that platelets actively sequester angiogenesis stimulators as well as inhibitors, and that there may be a higher organization of these opposing roles within platelet. This higher organization may facilitate the ability of platelets to modify angiogenesis in many angiogenesis-dependent disorders such as wound healing, atherosclerosis, tumor growth, macular degeneration and many others. Since the ability of platelets to enhance wound healing is restricted to intact platelets and does not extend to previously frozen platelets, the process most likely involves a reciprocal interaction between live, fully functional platelet and the wound microenvironment. Unlike other cells, platelets are destroyed by freezing. This proposal will a) characterize the molecular and cellular mechanisms by which platelets sequester and store angiogenesis regulators (Specific Aim 1); b) evaluate the mechanisms of release of these angiogenesis regulators from platelets (Specific Aim 2); c) test the potential therapeutic relevance of strategies designed to selectively release stimulators or inhibitors of angiogenesis from platelets in wound and tumor models (Specific Aim 3). The goal of these studies will be to provide a framework for development of novel targeted therapies for improvement of wound care, as well as for inhibition of tumor growth. It is expected that many agents that modify platelet function, secretion of proteins from platelets, and/or platelet adhesion will be applicable for management pathologic angiogenesis. PUBLIC HEALTH RELEVANCE: Platelets are very important in the formation of the provisional matrix that facilitates the growth of new vessels. This process is evident during physiological angiogenesis (such as wound healing or ovulation), as well as in pathological angiogenesis (such as tumor growth, arthritis, endometriosis, macular degeneration, retinopathy etc.). Exploring the similarities of these processes could be therefore very informative. As we have recently demonstrated, the ability of platelets to up- or down-regulate angiogenesis depending on the tissue needs is attributable to a higher organization of stimulators and inhibitors of angiogenesis within platelets. An improved understanding about this ability to down- regulate angiogenesis during wound healing or about the continued stimulation of angiogenesis in tumor growth is likely to lead to novel therapeutic targets. The immediate goal of our initiative will therefore be to improve the knowledge about the basic mechanisms of platelet-facilitated modulation of angiogenesis in wound healing and tumor growth. The anticipated benefit is that our efforts will lead to discovery of unique molecular targets that could then be studied in clinical trials, and lead to an accelerated improvement in the lives of children and adults, who face death from cancer, or disability due to chronic wounds.